The Estrogen-Related Receptor 3 (ERR3), also termed Estrogen-Related Receptor gamma (ERRγ), belong to the family of estrogen-related receptors, for which no natural ligand has yet been identified. Estrogen-related receptors belong themselves to the family of the Nuclear Receptors (NRs).
Orphan members of the nuclear receptor (NR) superfamily were initially identified by their high homology with the steroid or retinoid receptors and hypothesized to be ligand-regulated despite the lack of a known ligand (Willy et al., 1998; Giguere, 1999)). Meanwhile, for some of them, e.g. the peroxisome proliferator-activated receptors (PPARs), the constitutive androstane receptors (CARs), the pregnane X receptor (PXR), and recently the estrogen-related receptors (ERRs), synthetic or natural ligands have been identified (Kliewer et al., 1999; Tzameli et al., 2001; Tremblay et al., 2001; Coward et al., 2001).
To date, the family of estrogen-related receptors (ERRs) include three receptors, namely ERR1, ERR2 and ERR3.
As constitutive androstane receptors (CARs) and retinoid-related orphan receptors (RORs), ERRs constitutively activate transcription in eukaryotic cells (Hong et al., 1999; Xie et al., 1999; Chen et al., 2001).
ERR3 is the first orphan receptor identified because of its constitutive interaction with transcriptional activators. ERR1 and ERR2 were formerly identified by simply screening cDNA libraries for clones with homology with nuclear receptors.
The genes encoding ERRs exhibits a high degree of DNA sequence homology to the estrogen receptor (ER) and shows a considerable level of amino acid sequence identity with ER in both the DNA-binding domain (DBD) and the Ligand Binding Domain (LBD) (Giguere et al., 1988; Heard et al., 2000; Hong et al., 1999).
ERRs, including ERR3, can bind to functional estrogen response elements (EREs) in ER target genes such as lactoferrin (Yang et al., 1996) and aromatase (Yang et al., 1998), which shows that there exists a possible overlap between ERRs biology, and particularly ERR3 biology, and ER biology.
Several lines of evidence suggest that ERRs, including ERR3, are hormone-regulated. First, Vanacker et al. (1999) have observed that fetal calf serum contains a factor or factors that can stimulate ERRα basal activity by 12-fold. Second, Yang and Chen (1999) have reported that micromolar concentrations of the pesticides toxaphene and chlordane decrease ERRα basal activity.
Further, Coward et al. (2001) have reported that the estrogen diethylstilbestrol (DES) and the antiestrogens tamoxifen (TAM) and 4-hydroxytamoxifen (4-OHT) bind to ERR3 with submicromolar affinities and that 4-OHT repressed transactivation mediated by ERR3.
Also, Tremblay et al. (2001) have shown that DES interacts with both ERRα (ERR1), ERRβ (ERR2), and ERRγ (ERR3) to suppress coactivator binding and transcription from a reporter gene, and that the synthetic estrogen controls the differentiation of trophoblast cells in culture and in utero.
It has also been shown that ERR3 binds as a homodimer to direct repeats (DR) of the nuclear receptor half-site “5′-AGGTCA-3′”, to extended half-sites, and to the inverted estrogen response element.
Also, Hong et al. (1999) have reported that ERR3 binds specifically to an estrogen response element and activates reporter genes controlled by estrogen response elements, both in yeast and mammalian cells. According to these authors, expression of ERR3 in adult mouse is restricted; highest expression was observed in heart, kidney and brain. Further, in the mouse embryo, no ERR3 expression was observed at day 7, and highest expression occurred around the 11-15 day stages. These authors believe that ERR3 would have a unique role in development.
There is a need in the art to identify compounds which behave as agonists or antagonists of ERRs in order to provide to the public biologically active compounds exerting an enhancement or in contrast a decrease in the transcriptional-activating activity of ERRs, for example in pathologies wherein a dysfunction in the level of ERRs biological activity is detected or measured.
Such ERR3 agonist or, more likely, antagonist compounds would be biologically-active compounds useful in modulating the estrogenic response on:    fertility,    birth control,    bone remodeling,    breast cancer,    prostate cancer.